Th17 cells are a novel subset of T helper cells characterized by the production of IL-17. Th17 cells were shown to be important in mediating immune responses to variety of pathogens and responsible for development of several autoimmune diseases. Little is known about the role of Th17 cells during HIV infection. Given their potent functions both in microbial defense and promoting inflammation, especially at mucosal surfaces, their disturbance during HIV infection could have profound impact on the HIV pathogenesis. In preliminary studies we provide extensive evidence that a sizeable portion of human Th17 cells express CCR5 and are susceptible to HIV infection. We also found that in vivo Th17 cell numbers were reduced in all stages of HIV-infected subjects that were under treatment. Remarkably, Th17 cells were not significantly lower in untreated and viremic HIV positive subjects. These findings have led us to ask several interesting questions on perturbance of Th17 cells during HIV infection. Is the lower level of Th17 cells in treated and non-viremic HIV+ subjects due to chronic immune activation? Are there subsets of Th17 cells that are targeted by virus during viremic stage of the infection? Does Th17 cell numbers change after HIV+ naove subjects start treatment? Are there HIV-specific Th17 cells and do Th17 effector functions play a role against HIV infection? To answer these questions we propose the following specific aims to determine: 1) changes in Th17 cells and their relationship with other T cell subsets, in HIV-infected subjects, before and after initiation of treatment, 2) mechanisms that could explain lower levels of Th17 cells in treated HIV+ subjects with undetectable virus, 3) presence of HIV-specific Th17 cells in HIV+ individuals and whether these cells influence HIV replication through their effector functions. Together these approaches will be highly significant in understanding and identifying the mechanisms by which Th17 cells are regulated during HIV infection and their potential role in pathogenesis of HIV disease. The knowledge gained from these proposed aims may also allow us to use Th17 cells as a marker to predict the course of HIV disease stages and for developing novel therapeutic interventions or vaccine approaches that take advantage of Th17 subset during HIV infection. . PUBLIC HEALTH RELEVANCE: This project is aimed at understanding the role of a recently identified subset of human T lymphocytes called Th17 cells during HIV infection. Th17 cells have been shown to mediate major inflammatory conditions including several autoimmune diseases and they could contribute to pathogenesis of HIV disease. The knowledge gained from these studies may have important implications in regulating this lymphocyte subset during HIV infection and identify better predictive markers for HIV disease progression.